Blood-borne metastasis is a highly orchestrated and dynamic process initiated when cancerous cells disassociate from a primary tumor and migrate across vessel walls into the circulation. During their passage through the vascular system, tumor cells are exposed to mechanical and immunological stresses, which affect their ability to metastasize. Only tumor cells uniquely fit to overcome or even exploit the detrimental effects of hemodynamic forces and immunosurveillance will adhere to the vascular endothelium of distant organs, extravasate and successfully colonize these sites.
The adhesive interactions of circulating tumor cells (CTCs) with host cells including platelets, leukocytes and endothelial cells may regulate their extravasation from the vasculature. Platelets, by forming heterotypic complexes with tumor cells, may mask them from immune-mediated mechanisms of clearance. Palumbo et al., 105 BLOOD 178-185 (2005); Borsig et al., 99 PROC. NATL. ACAD. SCI. USA 2193-2198 (2002); Borsig et al., 98 PROC. NATL. ACAD. SCI. USA 3352-3357 (2001); and Nieswandt et al., 59 CANCER RES. 1295-1300 (1999) Alternatively, platelets may potentiate tumor cell adhesion to the vessel wall (Burdick et al., 287 J. PHYSIOL. CELL. PHYSIOL. 539-547 (2004) and release an array of bioactive compounds such as vascular endothelial growth factor at points of attachment to endothelium, thereby promoting vascular hyperpermeability and extravasation (Nash et al., 3 LANCET ONCOL. 425-430 (2002)). Moreover, polymorphonuclear leukocytes (PMNs) facilitate tumor cell extravasation in vitro (Slattery et al., 106 INT. J. CANCER 713-722 (2003); Starkey et al., 34 INT. J. CANCER 535-543 (1984)), and promote the arrest and deposition of tumors in the microvasculature of target organs in animal models (Starkey et al., 34 INT. J. CANCER 535-543 (1984)). PMN-facilitated tumor cell extravasation under dynamic flow conditions involves initial PMN tethering on the endothelium and subsequent arrest of free-flowing tumor cells by tethered PMNs. Lian et al., 295 AM. J. PHYSIOL. CELL PHSIOL. C701-707 (2008).
Selectins may facilitate cancer metastasis and tumor cell arrest in the microvasculature by mediating specific interactions between selectin-expressing host cells and ligands on tumor cells. The molecular and biochemical underpinnings of selectin-ligand interactions involved in heterotypic tumor cell-host cell adhesion events are not well understood. There is a need for new therapeutics and diagnostics for metastatic cancer.